Overview

Liver transplantation has evolved from a risky procedure with high morbidity and mortality to a standard treatment for patients with liver failure. Patients who undergo successful liver replacement have 5-year survival rates that exceed 70% (Muraji et al, 1997; see Chapter 97A, Chapter 97B, Chapter 97C, Chapter 97D, Chapter 97E ). Despite this dramatic improvement in outcome, a significant percentage of patients experience life-threatening complications that can result in the need for reoperation. As expertise in the procedure grows, surgeons are willing to attempt liver transplantation in patients who previously were considered poor candidates for surgery. Recipient portal vein thrombosis (PVT) was considered an absolute contraindication to surgery, but now transplantation is commonly performed in the presence of PVT (Shaked & Busuttil, 1991; Stieber et al, 1991).

As surgeons continue to develop new surgical procedures, such as transplantation of reduced-size and split-liver grafts and living-donor liver transplantation (LDLT), a new series of complications unique to these procedures is emerging (Broelsch et al, 2000; Emond et al, 1993). The incidence of hepatic artery thrombosis, bile leaks, and stricture is at least two times higher in patients who receive living-donor grafts compared with those who receive cadaveric grafts (Malago et al, 2003). Despite a higher morbidity rate in recipients of living-donor grafts, patient and graft survival are similar or superior to those observed with deceased donors (Fan et al, 2002; Lo et al, 2002; Pomposelli et al, 2006). This chapter reviews common early and late complications encountered during and after liver transplantation. Because complications after liver transplantation represent a continuum, most can occur at any time after surgery.

Procurement Injury to the Graft

The process of organ transplantation begins with identification of a suitable organ for a particular recipient. When an organ is identified, procurement teams are dispatched for recovery of various organs. In general, the liver procurement team dictates the conduct of dissection below the diaphragm, while the cardiac team works in concert with the thoracic team, if lungs and heart also are to be recovered. Because the infradiaphragmatic dissection takes considerably longer than the thoracic dissection, careful planning is required to minimize cold ischemia time for the heart and lungs, which are more time sensitive. The heart procurement team stays in contact with the recipient heart team to minimize total ischemic time.

Under ideal conditions, the conduct of the operation is orderly and well controlled; however, a patient who progresses to brain death rapidly can show cardiac instability and be difficult to manage. This situation can result in an expedited operation in which perfusion cannulae are hastily placed, and organ procurement rapidly follows. During such events, identification of appropriate anatomy is difficult, and technical errors are more likely to occur.

To increase the number of organs available, donation after cardiac death (DCD) is a new form of donation that is increasing in incidence (Chin et al, 2002). In this form of donation, a patient who is deemed hopeless but has not met criteria of brain death is allowed to die naturally after removal of supportive measures. After a period of usually 5 minutes of asystole, organs can be procured for transplantation. Despite the various periods of hypotension and warm ischemia that develop, outcomes with donation after cardiac death have been acceptable (Chin et al, 2002; Cooper et al, 2004). In liver grafts procured from DCD donors, increased biliary strictures and worse long-term graft survival have been suggested (D’Alessandro et al, 2004).

The most common injury during liver procurement is aberrant hepatic artery ligation and division. This injury occurs by failure to recognize a replaced or accessory right or left hepatic artery during hilar dissection or by unintentional division during organ removal. Such injuries are serious, because segments of the liver are not perfused during recovery and usually require reconstruction on the back table before reimplantation. An additional anastomosis on the back table prolongs ischemic time, increases the chances of thrombosis, and increases the need for retransplantation. Prolonged ischemic time, especially longer than 12 hours, increases the risk for graft loss and bile duct necrosis (Mor et al, 1993; Quiroga et al, 1991). To minimize dissection-related injuries, some authors prefer to use the en bloc method of removing abdominal organs, with back-table dissection (Imagawa et al, 1996). Regardless of the technique used, attention to detail and identification of the appropriate anatomy help avoid graft procurement injury.

Intraoperative Hemorrhage and Coagulopathy (See Chapter 70B)

All patients with end-stage liver disease come to the operating room with derangements in coagulation, and many present with severe portal hypertension. The combination of these two conditions results in a significant challenge for the surgeon and anesthesiologist. Patients who have undergone previous operations are at particular risk, because prolonged lysis of adhesions may greatly increase the duration of the operation, create additional raw surface areas for bleeding, and lead to derangements in temperature and fluid homeostasis. The net result is worsening coagulopathy, which creates a vicious cycle during the procedure.

Improvements in surgical techniques and better patient selection have led to the performance of liver transplantation without the need for blood transfusion in selected patients. The advent of the transjugular intrahepatic portosystemic shunt (TIPS) can significantly lower portal hypertension preoperatively and may help to reduce blood loss during transplantation (Forster et al, 1994); however, a misplaced TIPS in the vena cava or portal vein can be a life-threatening complication during liver transplantation. In these situations, TIPS removal is difficult and may lead to massive hemorrhage, if vascular control of the native vessels cannot be achieved.

In the presence of severe portal hypertension and underlying coagulopathy, the infusion of fresh frozen plasma and antifibrinolytic agents is the mainstay of therapy during liver transplantation (Palareti et al, 1991). These modalities cannot supplant the need for sound surgical technique with adequate control of all surgical bleeding sites. Bleeding observed after reperfusion may be related to poor initial graft function but also has been related to the release of heparin and heparin-like substances from the graft. Kettner and colleagues (1998) used heparinase-modified thromboelastography (TEG) to identify patients who developed bleeding secondary to the release of heparin-like substances. Such screening methods may help stratify patients at particular risk for the development of reperfusion fibrinolysis and may offer future therapeutic strategies to control coagulopathy encountered immediately after reperfusion (Kettner et al, 1998).

When medical strategies fail to halt reperfusion fibrinolysis, intraabdominal tamponade with laparotomy packs provides the most conservative management. If the graft functions well, and the patient responds to core temperature warming and continued resuscitation, packs usually can be removed within 24 to 48 hours. Prophylaxis against intraabdominal sepsis with parenteral antibiotics is of unproven benefit but may be prudent in the setting of immunosuppression.

Primary Graft Dysfunction or Nonfunction

Numerous conditions can interfere with the initial function of the allograft after transplantation, including donor-related, procurement-related, and recipient-related factors. Donor-related factors that can affect graft function adversely include hemodynamic instability, poor nutritional status, extremes of age, drug toxicity, and steatosis (D’Alessandro et al, 2004; Marsman et al, 1996; Washburn et al, 1996).

Although no uniform definition exists, the severity and prognosis for graft dysfunction vary considerably. The most ominous syndrome is primary graft nonfunction, which usually requires immediate retransplantation. In such instances, a progressive increase is typically seen in serum transaminase levels (>8000 IU/L) within the first 24 to 48 hours in association with diminished bile and urine output. In our practice, postoperative trends in the prothrombin time (PT) have been the most reliable predictor of graft function and outcome. Laboratory studies drawn immediately after surgery serve as the baseline: the PT should plateau and then trend toward normalization in a matter of days with good graft function; any increase in the PT portends a worse prognosis and may represent primary graft nonfunction, especially if this occurs rapidly. An elevated PT that neither increases nor decreases may suggest primary graft dysfunction; recovery usually occurs with time, if no additional insults occur, such as infection or rejection. In these situations, infusion of prostaglandin E₁ may be beneficial in resolving or preventing renal or graft dysfunction (Chavin et al, 1996; Klein et al, 1996).

In addition to trends in the PT, clinical assessment can be helpful in identifying patients with graft dysfunction or nonfunction. Resolution of hepatic encephalopathy, adequate urine production, and absence of metabolic acidosis are reassuring in the early postoperative period. In patients who have received significant quantities of blood products, the development of metabolic alkalosis may be a sensitive indicator of early graft function (Driscoll et al, 1987). Such indicators are based on the ability of the liver graft to process citrate in the administered blood products to bicarbonate; failure to metabolize citrate to bicarbonate may reflect early allograft dysfunction.

In patients with progressive graft dysfunction or nonfunction, early consideration for relisting with a higher urgency (status 1) may be the only way to salvage the patient and prevent mortality. In this situation, aggressive metabolic supportive measures are needed to prevent bleeding complications, maintain acid-base status, and prevent permanent brain injury.

Vascular Complications

Hepatic Artery Thrombosis

Vascular complications are a major source of morbidity and graft loss in liver transplant patients. Arterial complications, of which hepatic arterial thrombosis (HAT) is the most common, account for 64% to 82% of the vascular complications encountered (Bell et al, 1990; Leonardi et al, 2004). The overall incidence of HAT is 1.6% to 8% in various adult series, but it can be 15% to 26% in pediatric patients (Busuttil et al, 1991; Mazzaferro et al, 1989; Tan et al, 1988). The incidence of HAT in LDLT varies widely and is influenced by the type of graft, surgeon experience, and donor anatomy.

Doppler ultrasound (US) is the best screening method and should be used liberally in the first 2 weeks after transplantation with any change in graft function or significant elevation in bilirubin or transaminases. Because collateral blood flow through the gastroduodenal artery can result in a false-negative result, care must be taken to establish arterial flow within the hepatic parenchyma. In cases of suspected HAT revealed by US, confirmation should be made by celiac arteriography (Fig. 100.1) or multiphase computed tomography (CT). Failure to make a rapid diagnosis can result in hepatic necrosis and graft loss.

FIGURE 100.1 Hepatic artery thrombosis. The patient developed a rapid increase in serum transaminases in the early postoperative period. Ultrasound could not locate an intrahepatic arterial signal. Celiac arteriography shows left gastric and splenic arterial flow and fails to show any contrast in the liver. This is consistent with intimal dissection of the entire common hepatic artery. The T-tube within the common bile duct is visible.

Intimal dissection of the recipient hepatic artery down to the origin of the celiac axis is a common cause of intraoperative HAT. In these cases, immediate reconstruction with a donor iliac allograft is indicated (Fig. 100.2). Under no circumstances should the patient leave the operating room without a completely revascularized graft. When a donor iliac allograft is unusable or unavailable, an autogenous saphenous vein graft should be used. Rarely, an artificial conduit made from Dacron or expanded polytetrafluoroethylene can be used.

FIGURE 100.2 Hepatic artery reconstruction. With early diagnosis of hepatic artery thrombosis, immediate reconstruction with a donor iliac artery allograft can be performed. In this case, the iliac artery graft is anastomosed between the infrarenal aorta and liver allograft common hepatic artery.

The clinical presentation of HAT observed postoperatively ranges from a completely asymptomatic patient with minimal alterations in liver function to a critically ill patient with fulminant hepatic necrosis. A more common presentation of HAT is with postoperative biliary complications, including leaks and stricture formation (Margarit et al, 1998; Orons et al, 1995). Treatment for HAT in the early postoperative period is the same, whether symptoms are present or not: rapid reestablishment of arterial inflow should be attempted, which generally requires urgent operation with arterial reconstruction using a donor iliac artery allograft or autogenous graft material. Some authors have attempted thrombolysis using tissue plasminogen activator and urokinase, but this can be expected to be successful only when no technical factors are contributing to the thrombosis (Hidalgo et al, 1989). Hepatic artery intimal dissection is not amenable to thrombolytic therapy, and attempts at systemic thrombolysis waste valuable time and resources and worsen outcome. In most cases, 50% to 70% of patients ultimately require retransplantation (Langnas et al, 1991).

Biliary Complications

Biliary tract complications related to bile duct reconstruction previously were considered the Achilles heel of liver transplantation, but improvements in operative technique have reduced these complications markedly. Nevertheless, bile duct obstruction and leaks are the cause of approximately half of all technical failures after transplantation and require reoperation in 10% to 20% of patients (Lerut et al, 1987). In general, recipients of living-donor grafts have an incidence of biliary complications approximately two times higher than recipients of cadaveric grafts (Pomfret et al, 2001). HAT is associated with biliary complications and may explain the increased incidence among living-donor graft recipients.

Biliary Stricture or Obstruction

Biliary obstruction occurs in approximately 7% to 15% of patients after liver transplantation (Klein et al, 1991; Lerut et al, 1987). As with leaks, the site of obstruction aids in determining the cause. Anastomotic stricture accounts for 50% of obstruction cases and can occur early in the postoperative period, secondary to edema, or later, as a result of compromised blood supply (Fig. 100.3). Biliary strictures usually present within weeks but may occur years after transplantation. Two types of biliary obstruction usually are found: anastomotic and nonanastomotic. Nonanastomotic obstruction or stricture can be caused by or associated with bile duct ischemia or sludge and debris that can accumulate in the biliary system after transplanting (Fig. 100.4).

FIGURE 100.3 Biliary stricture. This patient had a previously created Roux-en-Y hepaticojejunostomy and now has an anastomotic stricture. Note the dilated intrahepatic ducts. Percutaneous access of the Roux-en-Y limb affords the ability to make the diagnosis and treat with balloon dilation. Using this technique, placement of transhepatic catheters is avoided.

FIGURE 100.4 Nonanastomotic biliary stricture observed from ischemic injury to a liver graft in a patient who received a liver from a donor who died from cardiac death rather than brain death. Donation after cardiac death (DCD), rather than after brain death, is an attempt to expand the organ donor pool; but such grafts are more prone to ischemic injury problems such as bile duct stricture.

The diagnosis of biliary stricture or obstruction is implied by an obstructive pattern on routine liver function tests. Commonly, patients are seen with constitutional symptoms of rigor, fever, headache, and fatigue. Occasionally, patients present with severe symptoms of cholangitis and sepsis. Because patients with “mild” signs and symptoms also may reflect the presence of any number of serious conditions—acute rejection, HAT, cytomegalovirus (CMV) infection, or recurrent disease—diagnosis can be difficult. To ascertain the correct diagnosis rapidly, a series of diagnostic studies that include abdominal US, cholangiography, and liver biopsy is obtained immediately after the onset of abnormal clinical signs and symptoms (Kuo et al, 1994).

Regardless of the method used to reestablish the biliary continuity, the most common site of a biliary stricture in the posttransplantation setting is at the biliary anastomosis. Technical error during reconstruction is an important causative factor, but the patency of the hepatic artery also should be assessed, particularly in pediatric recipients. Other factors that have been implicated in the development of biliary stricture include ABO incompatibility, prolonged preservation times, chronic rejection, CMV infections, and recurrence of primary ductal disease, such as sclerosing cholangitis (Feller et al, 1996; Greif et al, 1994; Sebagh et al, 1995).

Biliary reconstruction after LDLT is by Roux-en-Y hepaticojejunostomy or duct-to-duct anastomosis (Kawachi et al, 2002). Anastomotic leak or stricture is generally two times more common after living-donor versus cadaveric liver transplantation (Miller et al, 2001). Nonanastomotic strictures can occur in the hilar region or intrahepatically. As with anastomotic strictures, thrombosis of the hepatic artery or one of its branches should be suspected. Nonanastomotic strictures also have been reported in association with chronic ductopenic rejection, ABO blood group incompatibility, and as a result of ischemia-reperfusion injury associated with allograft preservation (Sanchez-Urdazpal et al, 1992).

After appropriate fluid resuscitation and antibiotic coverage, we recommend ERC to confirm the diagnosis and to implement treatment with immediate stenting if possible. Failure to cross the stricture through endoscopic means requires PTC or surgical revision with Roux-en-Y hepaticojejunostomy. Intrahepatic strictures are best treated with percutaneous balloon dilation. Rarely, stents are needed to achieve a satisfactory outcome (Colonna et al, 1992).

Renal Dysfunction

Renal dysfunction is observed to some degree in almost every patient who undergoes liver transplantation (Baliga et al, 1992; Lam et al, 2004). Early renal dysfunction usually is characterized by a period of oliguria with a transient increase in serum creatinine but can also be manifested as anuria with acute renal failure. Risk factors include preexisting renal dysfunction and primary graft nonfunction. In patients with normal preoperative serum creatinine and good initial graft function, the usual mechanism is prerenal azotemia secondary to periods of hypotension and hypovolemia during the operative procedure. An additional insult to renal function can be incurred by the administration of nephrotoxic agents, especially the calcineurin inhibitors (CNIs) cyclosporine and tacrolimus; renal failure induced by CNIs occurs in approximately 5% of transplanted patients (Myers et al, 1986).

Although the etiology of renal failure in transplant patients can be multifactorial, long-term exposure (dose/time) to CNIs is a clear risk factor. As a result, there has been increasing interest in automatic dose reduction in patients many years out from transplantation and in those showing signs of progressive renal dysfunction. Another strategy to reduce calcineurin renal toxicity has been substitution of the immunosuppressive regimen by drugs that do not cause renal dysfunction, such as the mammalian target of rapamycin (mTOR) inhibitors.

Sirolimus (rapamycin) is a macrocyclic antibiotic originally developed as an anticandidal and antitumor agent (Vezina et al, 1975). It is often used for renal sparing but has the disadvantage of increasing the risk for dyslipidemia and impaired wound healing. The impairment of wound healing may be related to alterations in vascular endothelial growth factor (VEGF) and may explain the apparent benefit of sirolimus in reducing cancer formation in patients (Fuereder et al, 2010). Because sirolimus has been associated with early hepatic artery thrombosis (HAT) after liver transplantation, the manufacturer recommends waiting at least 4 weeks after transplantation before initiating therapy.

Posttransplantation renal failure so acute as to require dialysis is uncommon, unless the patient is diagnosed with preexisting hepatorenal syndrome or severe hypotension, and hemorrhage is encountered during surgery that results in acute tubular necrosis. In our experience, dialysis for these patients is best performed with continuous venovenous hemodialysis using a dedicated, large-bore, double-lumen venous access device. Recovery of normal renal function usually is achieved within 2 weeks, if no other metabolic stress is incurred.

Fluid and Electrolyte Disturbances

Fluid and electrolyte disturbances and alterations in acid-base status are universal after liver transplantation. Preoperative protein calorie malnutrition and end-stage liver disease lead to derangements in total body water and electrolyte balance that are worsened initially by the metabolic stress of surgery and massive fluid and blood product resuscitation. The rapidity of recovery depends in large part on the patient’s renal and liver allograft function postoperatively. For a patient with stable postoperative renal and liver graft function, little metabolic manipulation is required to correct such derangements.

The early development of metabolic alkalosis secondary to metabolism of citrate in blood products is a favorable sign of graft function but can be serious if alkalemia develops (Driscoll et al, 1987). In this situation, judicious replacement of chloride in the form of hydrogen chloride is warranted.

Excess total body water and excess sodium are best treated with gentle diuresis with furosemide. Careful repletion of potassium should be instituted, but it must be monitored closely in the setting of medications such as tacrolimus, which tends to increase serum potassium levels (Oishi et al, 2000). Derangements in serum calcium, magnesium, and phosphorus are common in patients with cirrhosis and should be repleted to avoid neurologic, skeletal, and cardiac muscle dysfunction.

Acute Cellular Rejection

In the early days of liver transplantation, the importance of rejection was overshadowed by technical complications. As surgical technique has evolved, with concomitant improvement in graft preservation, rejection has taken on greater clinical importance. Acute cellular rejection is defined as an acute deterioration in allograft function associated with specific histologic changes in the liver allograft. These changes include a mixed inflammatory cell infiltrate, predominantly lymphocytes, that involves the portal triads and disrupts the biliary, hepatic artery, and portal venous endothelia (endotheliitis) (Sedivy et al, 1998).

The incidence of acute rejection is approximately 45% (range, 24% to 80%), depending on the series reported. Although acute rejection has little to no impact on mortality, significant morbidity results in increased hospitalization and higher overall costs (Bucuvalas et al, 2001; Khettry et al, 2002). In the early stage, most patients are asymptomatic, but a variety of clinical signs and symptoms may develop that include fever, abdominal pain, malaise, fatigue, and poor appetite.

The earliest laboratory indicator of acute rejection is elevated bilirubin level, which may be associated with a modest increase in alkaline phosphatase and aminotransferase levels. PT and serum albumin levels are usually unaffected. Because laboratory measurements are neither sensitive nor specific for acute cellular rejection, liver histology obtained from a percutaneous biopsy specimen remains the standard for the diagnosis of cellular rejection (Khettry et al, 2002).

The initial treatment for acute cellular rejection includes high-dose pulse steroids, which is successful in approximately 80% to 90% of cases (Klintmalm et al, 1989). OKT3, a murine monoclonal antibody to the CD3 antigen–receptor complex, is reserved for the approximately 10% to 20% of patients whose acute cellular rejection cannot be not reversed with high-dose corticosteroid therapy. The major risks posed by using this treatment for acute cellular rejection include increased susceptibility to infection and the association between OKT3 use and posttransplantation lymphoproliferative disease (PTLD; Deschler et al, 1995). In addition, a severe systemic inflammatory response can be initiated from OKT3 infusion that can lead to pulmonary edema, hypotension, and shock.

Chronic ductopenic rejection affects approximately 10% of liver transplant patients. Ductopenic rejection rarely occurs during the first 2 months after liver transplantation; it is defined as loss of bile ducts in more than 50% of portal tracts, when 20 or more portal tracts are available for evaluation, and is diagnosed on the basis of histologic criteria (van Hoek et al, 1992). In addition, arteriopathy has been described that affects large and medium-sized arteries, characterized by foam-cell infiltration of the intima. The most important manifestation of chronic rejection, the term ductopenic rejection is used synonymously with the histologic description vanishing bile duct syndrome. No treatment exists with the exception of retransplantation (Koukoulis et al, 2001).

Infection

With few exceptions, all patients who undergo transplantation are committed to lifelong immunosuppression therapy to prevent graft rejection. Inadequate immunosuppression can result in graft loss, whereas injudicious use of immunosuppression can result in life-threatening infection or the development of PTLD. A tenuous balance exists between the proper amount of immunosuppression to prevent rejection and minimization of the risk for nosocomial and opportunistic infection. Despite better understanding of the immune response and proliferation of more selective immunosuppressive agents, approximately two thirds of transplant patients experience at least one episode of serious infection, which accounts for more than half of the observed mortality associated with liver transplantation (Kibbler, 1995).

Risk factors for postoperative infection after liver transplantation include those incurred from the donor, recipient, and intraoperative course: donor and recipient viral status, underlying medical comorbidities, and nutritional status all can contribute. Prolonged surgery with massive blood loss, prolonged ischemia time, and violation of the gastrointestinal tract also are risk factors for nosocomial infection (George et al, 1992).

Bacterial infections tend to occur within the first month after liver transplantation and vary from center to center (range, 35% to 68%) (Kibbler, 1995; Kusne et al, 1992). Early risk factors include prolonged operating time, indwelling catheters, biliary obstruction, PVT, and poor graft function. In addition, vascular ischemia, recurrent hepatitis C virus (HCV) infection, patient exposure to resistant organisms, and chronic rejection can contribute to nosocomial infection (Singh et al, 1997). Common bacterial pathogens include gram-negative organisms found in the bile (Escherichia coli, Enterobacter spp., Pseudomonas spp.) and gram-positive organisms (S. aureus, coagulase-negative staphylococci, and group D streptococci). Rarely, S. aureus can result in the development of toxic shock syndrome in the early postoperative period. Listeria, Nocardia, and Legionella are uncommon but significant pathogens (George et al, 1992).

Viral infections are common in immunocompromised patients after transplantation. In addition to the more common viral infections described here, other equally important but less common viral infections can be devastating to immunocompromised transplant patients; these include human immunodeficiency virus (HIV), adenovirus, influenza, and respiratory syncytial virus (RSV). In addition, transplant patients are at risk for acquiring viral hepatitis from infected organs, blood transfusions, and illicit drug use.

Cytomegalovirus (CMV) infection is the single most important infection observed in organ transplant patients. An asymptomatic infection in the general population, CMV attains significant potential severity in immunosuppressed transplant recipients and is the most important pathogen in clinical transplantation (Kusne & Shapiro, 1997). CMV disease usually occurs 30 to 50 days after transplantation, with clinical manifestations that include fever, malaise, arthralgia, leukopenia and thrombocytopenia, hepatitis, interstitial pneumonitis, enterocolitis, and disseminated disease. Differentiation between CMV disease and CMV infection is clinically important: CMV disease is defined as a histologically evident invasive CMV infection or a positive CMV culture from deep tissue specimens—liver biopsy, endoscopic mucosal biopsy or brushing, bronchoscopic mucosal biopsy or brushing—in the setting of clinical manifestation. The presence of positive blood, body fluid, or serologic tests is insufficient to establish the diagnosis of CMV disease. Liver biopsy with immunostaining using a monoclonal antibody against CMV antigen enables early diagnosis. Common histologic findings include hepatocyte necrosis, parenchymal microabscesses, and a magenta-colored intranuclear inclusion surrounded by a clear halo, the so-called owl’s eye nucleus (Everson & Kam, 1997).

Risk factors for the development of CMV disease include a seronegative recipient who received an organ from a seropositive donor, the use of antilymphocyte antibody therapy (particularly OKT3), and retransplantation. In general, the level of immunosuppressive therapy influences manifestation of CMV infection (Furukawa et al, 1996). Chronic CMV infection with persistent CMV replication within hepatocytes is associated with cholestatic hepatitis and vanishing bile duct syndrome.

Patients who manifest CMV disease are treated with a reduction, if possible, of the immunosuppressive regimen, particularly tapering of the steroid dose. For years, intravenous ganciclovir had become the mainstay of therapy and is safe and effective for prophylaxis and treatment. Occasionally, foscarnet is required as an alternative in cases of ganciclovir resistance, but it is less well tolerated and can be nephrotoxic.

Prophylaxis against CMV disease using oral and intravenous ganciclovir after transplantation has been effective. Other prophylaxis regimens using intravenous gancyclovir plus oral acyclovir for 3 months after transplantation or oral acyclovir used alone have been less successful (Nakazato et al, 1993; Oldakowska-Jedynak et al, 2003). More recently, prevention and treatment of mild CMV infection using oral valganciclovir has been demonstrated to be as effective as intravenous ganciclovir (Eid et al, 2010). Because of the effectiveness of oral valganciclovir, most transplant centers have switched to prophylactic regimens that range from 3 to 6 months of daily oral treatment (450 or 900 mg, depending on renal function). Side effects are minimal, but leukopenia can occur. Late-onset CMV disease remains a potential problem, especially in patients on higher doses of immunosuppression and in high-risk groups, whose donor was CMV positive when the recipient was CMV negative (CMV D+/R−).

Herpes simplex seropositivity is present in most patients undergoing liver transplantation. Herpes simplex infection observed postoperatively usually is related to immunosuppression-induced reactivation. Herpesvirus infection usually manifests as a mild mucocutaneous oral or genital disease that responds to acyclovir treatment; however, prompt recognition is important to prevent progression to lethal disseminated disease or fulminant hepatitis with coagulopathy, disseminated intravascular coagulation, and death. Graft involvement is diagnosed by a characteristic histologic picture on liver biopsy.

Epstein-Barr virus (EBV) belongs to the herpes family, and infection in a transplant patient is characterized by a mononucleosis-like syndrome that differs from that observed in the normal host by the absence of a heterophil antibody response and the infrequency of pharyngitis or splenomegaly (Alshak et al, 1993). The clinical significance of EBV infection in a liver transplant patient has to do with its role in the pathogenesis of PTLD (Manez et al, 1997), the development of which is thought to reflect the unrestricted proliferation of B cells stimulated by EBV infection. The incidence and treatment for established PTLD are discussed later.

Opportunistic infections also are commonly encountered. The incidence of clinically significant fungal infection is 20% to 25% in liver transplant recipients. Risk factors for fungal infection include poor nutrition status, retransplantation, bacterial infection with prolonged antibiotic use, high doses of immunosuppression, and biliary reconstruction using Roux-en-Y hepaticojejunostomy (Castaldo et al, 1991).

Disseminated fungal infection with Candida or Aspergillus can be difficult to diagnose and is associated with a high mortality rate in these patients. If the suspicion of invasive fungal infection is high, every effort should be made to obtain histologic or culture evidence to establish early diagnosis. Aspergillus, the second most frequent fungal infection in transplant patients after Candida, is acquired by inhalation and colonizes the airways before causing invasive disease. Aspergillus is angioinvasive and tends to disseminate to the central nervous system (CNS) and can cause infarcts and cavitation in the lungs. The incidence of invasive aspergillosis is approximately 1% in liver transplant recipients, with a mortality rate close to 100% despite adequate treatment (Kusne et al, 1992).

Infection by Cryptococcus neoformans usually occurs months to years after transplantation and affects approximately 0.25% of liver transplant patients (Patel et al, 1996). Because signs and symptoms may be subtle, delayed diagnosis is common. Symptoms that bring the patient to medical attention include changes in mental status, headache, and fever. In our experience, one patient was seen initially with lesions in the CNS and large cavitating masses in the thorax that required operative removal.

Pneumocystis carinii pneumonia was previously a common pathogen in the immunocompromised host. With the introduction of routine use of prophylaxis with daily low-dose oral trimethoprim/sulfamethoxazole for 6 to 12 months, or aerosolized pentamidine in patients intolerant to trimethoprim/sulfamethoxazole, the incidence of P. carinii pneumonia has decreased dramatically. Because prophylaxis has been so effective, P. carinii pneumonia has occurred almost exclusively in patients who do not receive prophylaxis. Given the low morbidity associated with the prophylactic regimens, no patient should be excluded.

Legionella pneumophila is an uncommon cause of pneumonia in patients after liver transplantation. As in the normal host, the source of legionellosis is usually the water supply. Traditionally, treatment of Legionella pneumonia has been with erythromycin, but quinolones also have been proven effective and have the advantage of not interacting with immunosuppressive agents such as cyclosporine and tacrolimus.

Posttransplantation Lymphoproliferative Disorder

PTLD is a life-threatening complication of chronic immunosuppression. Lymphoproliferative disorders have been strongly associated with the replication of EBV in B cells induced by enhanced immunosuppression (Manez et al, 1997; Newell et al, 1996); this has been observed primarily in patients who have received more than one course of polyclonal antilymphocyte globulin or monoclonal OKT3 (Davis et al, 1995). An association with CMV infection also has been noted. The incidence of PTLD varies from 1% to 3% among liver transplant recipients, and prognosis depends on the histologic characteristics of the tumor. Polyclonal PTLD is treatable with discontinuation of immunosuppression with relatively low risk of rejection (Hurwitz et al, 2004). Monoclonal PTLD is more difficult to treat and can result in death. Antibody against CD20 represents a novel approach in treating monoclonal PTLD, with favorable outcome (Yedibela et al, 2003; Zompi et al, 2000). The clinical presentation of PTLD varies and includes fever, malaise, and lymphadenopathy with or without tonsillitis. In addition, gastrointestinal bleeding, perforation, or obstruction; hepatocellular dysfunction; and CNS manifestations, such as seizures, mental status changes, and focal neurologic symptoms also have been described.

Lymphoproliferative disorders occurring after transplantation have characteristics distinct from the lymphoproliferative disorders that occur in the general population. Non-Hodgkin lymphoma accounts for 65% of lymphomas in the general population, compared with 93% in transplant recipients. These tumors are mostly large-cell lymphomas, and most are of the B cell type. Extranodal involvement is common and occurs in approximately 70% of cases (Zompi et al, 2000).

Treatment of polyclonal PTLD consists of reduction of immunosuppressive medications and antiviral therapy (Starzl et al, 1984). Patients with monoclonal PTLD and patients with polyclonal disease that does not respond to reduced immunosuppression have been treated with radiation, chemotherapy, and occasionally surgical resection. Therapy using monoclonal antibody against CD20 shows promising results for patients with monoclonal PTLD (Dotti et al, 2001; Zompi et al, 2000).

Acute Immunosuppressive Drug Toxicity

Immunosuppression after transplantation must achieve a balance between the beneficial effects of the drugs in preventing or reversing rejection and the dangers of excess immunosuppression with the development of acute toxicity symptoms, nosocomial infection, and lymphoproliferative disorders. The most common agents used for immunosuppression in liver transplant patients are the CNIs cyclosporine and tacrolimus (FK506) in combination with steroids. Azathioprine is used less frequently in liver transplant than in kidney transplant recipients, who usually receive triple-drug therapy. Mycophenolate mofetil has essentially replaced azathioprine in the immunosuppression regimen after liver and kidney transplantation. After the initiation of immunosuppression therapy, development of infection and acute toxicity are usually seen early during treatment, whereas lymphoproliferative disorders and other malignancies are long-term sequelae as previously mentioned.

In addition to PTLD, chronic immunosuppression has been associated with an increased frequency of many other neoplasms, including basal skin cancer, non-Hodgkin lymphoma, Kaposi sarcoma, uterine cervical carcinoma, and carcinomas of the external genitalia (Busuttil et al, 1991). As with PTLD, patients who received repeated doses of antilymphocyte antibody have a particularly high incidence of neoplasms (Millis et al, 1995). Long-term use of steroids, particularly at high doses, is associated with obesity, hypertension, bone disease, glucose intolerance, pancreatitis, muscle weakness, hirsutism, and fluid and sodium retention; in children, growth retardation is a major problem (Busuttil et al, 1991).

The side-effect profiles of cyclosporine and tacrolimus are similar and include gastrointestinal disturbances, headache, and tremor. Gingival hyperplasia and hirsutism are encountered frequently during cyclosporine and steroid treatment, whereas glucose intolerance is reported more often with tacrolimus treatment than with cyclosporine therapy. Hyperkalemia, hyperuricemia, hypophosphatemia, and hypomagnesemia are manifestations of renal tubular dysfunction and usually can be controlled by adjusting the dose according to drug levels. Nephrotoxicity is the most clinically significant adverse effect of both drugs and is manifested as acute azotemia. This effect is largely reversible after reducing the dose of the drug and providing adequate hydration. Occasionally, progressive chronic renal disease can develop, which is usually irreversible. In such a situation, dialysis or kidney transplantation is required. Other renal effects of cyclosporine include chronic tubular dysfunction and, rarely, hemolytic uremic syndrome (Cohen et al, 2002).

Recurrent Hepatitis (See Chapter 64)

In patients who develop cirrhosis secondary to chronic hepatitis B virus (HBV) infection, the recurrence rate as evidenced by signs of viral replication (HBV e-antigen–positive or positive titers of HBV DNA) is approximately 80% to 90% in the first year. Given the almost universal recurrence of HBV antigenemia in the early postoperative period, some authors have questioned the utility of liver replacement in these patients. With the advent of hepatitis B immunoglobulin (HBIg) and other adjuvant therapies, such as interferon and lamivudine, to prevent recurrent disease, transplantation now is routinely offered to patients with chronic HBV infection, with excellent results (Dodson et al, 2000; Grellier et al, 1996).

Recurrent HCV infection is universal after liver transplantation (Gordon et al, 1997). In 90% of patients, hepatitis can be confirmed on routine biopsy. Of these, 60% have mild hepatitis, whereas 30% develop a more severe pattern seen on histologic examination. In patients with severe recurrent HCV, 20% go on develop to cirrhosis within 5 years (Gordon et al, 1997). Of 100 patients with HCV infection who are transplanted, approximately 6 will require retransplantation (Gordon et al, 1997). Prophylaxis with ribavirin and interferon has been shown to be beneficial in reducing viral loads to zero, with significant prolongation of graft survival (Ahmad et al, 2001). Given the epidemic growth in HCV infection, it is likely to dominate the indications for liver replacement for years to come.

Bone Disease

Almost all patients who undergo liver transplantation have some degree of hepatic osteodystrophy. The mechanism seems to vary according to the underlying disease. The causes are multifactorial and include corticosteroid therapy, bed rest, and cholestasis. Osteoporosis is particularly common 3 to 6 months after transplantation; however, by the end of the first year after transplantation, patients start gaining bone density. This late improvement is probably because of a reduction in corticosteroid therapy and the resolution of the pretransplantation condition that was deleterious to skeletal health. Atraumatic bone fractures are more frequent within the first 6 months after transplantation as a result of the extensive bone loss that occurs during this period (Navasa et al, 1996). Avascular necrosis and vertebral body collapse may also occur.

Neuropsychiatric Complications

Severe neuropsychiatric changes can occur after liver transplantation. In addition to the acute neurophysiologic changes associated with fluid and electrolyte shifts during the perioperative period, anxiety and depression are common psychiatric conditions observed in many transplant patients. Seizures, alterations of the levels of consciousness, and infections of the CNS are infrequent but are significant causes of morbidity and mortality. Encephalopathy observed after transplantation can be related to poor initial graft function, but it is more commonly multifactorial in etiology. Metabolic derangements, hypoxia, sedation, and drug interactions all can contribute.

Neurologic signs and symptoms associated with immunosuppression toxicity related to cyclosporine and tacrolimus include tremors, headaches, and seizures. These can be avoided by close monitoring of drug levels. High-dose steroids can result in emotional lability or mania. Any patients presenting with new neuropsychiatric symptoms should have a cranial CT scan and lumbar puncture to rule out other causes of mental status changes, such as intracerebral bleeding or an infectious etiology.

Hypertension and Hyperlipidemia

Common sequelae of immunosuppression are the development of hypertension and hyperlipidemia in the posttransplantation period (Fernandez-Miranda et al, 1998). As patient survival improves, the consequences of these conditions have greater importance on long-term prognosis. Hypertension is observed in approximately 70% of liver transplant recipients at 1 year, and nearly 40% of patients develop sustained hypercholesterolemia and hypertriglyceridemia during the same time period. The pathophysiology of posttransplantation hyperlipidemia is complex. Rapamycin immunosuppression does not cause glucose intolerance, but it can lead to hyperlipidemia (Trotter, 2003). Omega-3 fatty acids found in fish oil can reduce hypertriglyceridemia significantly. In our experience, oral supplementation with over-the-counter fish oil capsules (4 to 6 g/day) has shown a dose-response reduction in serum triglycerides. Given the additional risk of development of coronary artery and peripheral vascular disease, aggressive therapy—with dietary changes, exercise, and medication—is indicated.

Summary

Liver transplantation is a lifesaving treatment modality for patients with end-stage liver disease. The wide range of comorbidities that develop preoperatively contributes significantly to the development of postoperative complications. Aggressive use of immunosuppression is successful in preventing rejection in many cases, but therapy can be complicated by the development of life-threatening neoplasms. Recent trends favor significant reduction of immunosuppression over time and early withdrawal of steroids, once the mainstay of immunosupressive regimens. The reduction of immunosuppression in selected patients and early withdrawal of steroids have significantly reduced morbidity and life-threatening complications.

Positive outcomes after liver transplantation require a multidisciplinary team approach that comprises surgeons, transplant coordinators, hepatologists, and internists to maintain constant surveillance for the inevitable complications that arise. Early diagnosis with rapid treatment provides the best opportunity for disease-free survival.